Targeted drug delivery means are particularly desirable where toxicity or bioavailability of the pharmaceutical compound is an issue. Specific drug delivery methods and compositions that effectively deposit the compound at the site of action potentially serves to minimize toxic side effects lower dosing requirements and decrease therapeutic costs. In this regard, the development of such systems for pulmonary drug delivery has long been a goal of the pharmaceutical industry.
The three most common systems presently used to deliver drugs locally to the pulmonary air passages are dry powder inhalers (DPIs), metered dose inhalers (MDIs) and nebulizers. MDIs, the most popular method of inhalation administration, may be used to deliver medicaments in a solubilized form or as a dispersion. Typically, MDIs comprise a Freon or other relatively high vapor pressure propellant that forces aerosolized medication into the respiratory tract upon activation of the device. Unlike MDIs, DPIs generally rely on the patient's inspiratory efforts to introduce a medicament in a dry powder form to the lungs. Finally, nebulizers form a medicament aerosol to be inhaled by imparting energy to a liquid solution. More recently, direct pulmonary delivery of drugs during liquid ventilation or pulmonary lavage using a fluorochemical medium has also been explored. While each of these methods and associated systems may prove effective in selected situations, inherent drawbacks, including formulation limitations, can limit their use.
A key development, which has elevated the importance of pulmonary drug delivery systems, has been the emergence of new drugs derived from biotechnology (e.g. peptides, proteins, oligonucleotides and plasmids). The systemic delivery of these biopolymers has proven difficult, owing to their large molecular size, high surface charge, poor chemical and enzymatic stability, and low permeability across various absorption barriers of the body. Because of their low bioavailability by oral and transdermal routes of administration, drugs such as peptides are currently administered primarily by infusions or frequent injections. The development of less invasive methods for delivering peptides and other biopolymers represents a large focus of current drug delivery research, and a number of sites of administration are being explored, including enhanced oral, nasal, and pulmonary delivery.
As indicated above, nebulizers are frequently used for drug delivery to the human lung and are particularly useful for the treatment of hospitalized or nonambulatory patients. There are two main classes of devices: air jet nebulizers and ultrasonic nebulizers. In air jet nebulizers, compressed air is forced through an orifice. A liquid may then be withdrawn from a perpendicular nozzle (the Bernoulli effect) to mix with the air jet to form droplets. A baffle (or series of baffles) within the nebulizer is used to facilitate formation of the aerosol cloud. In contrast, ultrasonic nebulizers rely on the generation of ultrasound waves in an ultrasonic nebulizer chamber by a ceramic piezoelectric crystal that vibrates at a precise frequency when electrically excited. The ultrasonic energy sets up high-energy waves in the nebulizer solution, facilitating generation of an aerosol cloud.
Formulations for nebulization typically comprise aqueous-based solutions. Assuming that the solubility and stability of the active drug are adequate, an aqueous-based formulation administered by nebulization is reasonable when the estimated minimal effective dose exceeds about 200 μg. Continuous nebulization has long been an option for the delivery of topical lung therapy for the treatment of various lung diseases such as asthma, chronic obstructive pulmonary disease, emphysema, and bronchitis. More recently, proteins such as DNase have been delivered by conventional jet nebulizers for their local effect on the lung. Unfortunately, continuous nebulization is an intrinsically inefficient way to deliver aerosolized medication. This fact is underscored by the observation that doses of bronchodilators delivered using nebulizers are three orders of magnitude greater than a bioequivalent dose delivered by MDI or dry powder generator. In addition to concerns with respect to device efficiency, concerns also exist with regards to changes in the formulation during the nebulization process. For example, drug concentration in the reservoir solution of an air-jet nebulizer often increase over time. Moreover, a change in drug concentration may imply a change in osmolality of the aqueous solution, and hyperosmolar nebulizer solutions have been shown to cause bronchoconstriction.
In terms of pulmonary delivery of bioactive agents to the systemic circulation via nebulization, most of the research has focused on the use of portable hand-held ultrasonic nebulizers, also referred to as metered solution nebulizers. These devices should not be confused with hand-held nebulizers which require several minutes per treatment. These devices, generally known as single-bolus nebulizers, aerosolize a single bolus of medication in an aqueous solution with a particle size efficient for deep lung delivery in one or two breaths. These devices fall into three broad categories. The first category comprises pure piezoelectric single-bolus nebulizers such as those described by Mütterlein, et. al., (J. Aerosol Med. 1988; 1:231). In another category, the desired aerosol cloud may be generated by microchannel extrusion single-bolus nebulizers such as those described in U.S. Pat. No. 3,812,854. Finally, a third category comprises devices exemplified by Robertson, et. al., (WO 92/11050) which describes cyclic pressurization single-bolus nebulizers. Each of the aforementioned references is incorporated herein in their entirety.
While such devices are an improvement over conventional hand-held nebulizers that require treatment times of several minutes, they are somewhat limited by the fact that they employ multidose reservoirs. This is problematic for protein delivery applications where the product must remain sterile throughout the therapy program. At the very least use of these multidose reservoirs would require the use of preservatives, and even this approach is unlikely to be satisfactory under all product usage scenarios. In order to overcome some of these limitations, a unit dose system has recently been described by Schuster, et, al., (Pharm. Res. 1997; 14:354 which is incorporated herein). However, problems remain even with such unit dose systems. For example, a pitfall with devices for the delivery of bioactive agents to the systemic circulation is that the bioactive agent must have long-term stability in an aqueous phase. This is possible only for a select few peptides and proteins.
Accordingly, it is an object of the present invention to provide methods, compositions and systems for the effective pulmonary delivery of bioactive agents using nebulizers.
It is a further object of the present invention to provide methods and compositions for the stabilization of bioactive agents to be delivered using a nebulizer.
It is yet another object of the present invention to provide methods and preparations that advantageously allow for the efficient delivery of bioactive agents to the systemic circulation of a patient in need thereof.